Method and composition for combatting fungus with fungicidally-active pyrimidine derivatives

ABSTRACT

A method and composition are provided for combatting fungus of plants and animals wherein there is applied to the fungus a biologically-active pyrimidine derivative.

United States Patent [191 Snell [73] Assignee: Imperial ChemicalIndustries Limited, London, England [22] Filed: Feb. 9, 1971 [21] Appl.No.: 114,079

Related US. Application Data [63] Continuation-impart of Ser. No.624,126, March 20,

1967, abandoned.

[30] Foreign Application Priority Data Mar. 31, 1966 United Kingdom14266/66 Mar. 31, 1966 United Kingdom 14267/66 1 Sept. 16, 1975 [52] US.Cl 424/200; 260/256.5 R; 71/3 [51] Int. Cl. AOlN 9/36 [58] Field ofSearch 260/256.5 R; 424/200;

[56] References Cited UNITED STATES PATENTS 3,287,453 ll/1966 McHattie260/256.5 R

Primary Examiner-.lames 0. Thomas, Jr. Attorney, Agent, or FirmCushman,Darby & Cushman [57 ABSTRACT A method and composition are provided forcombatting fungus of plants and animals wherein there is applied to thefungus a biologically-active pyrimidine derivative.

2 Claims, N0 Drawings METHOD AND COMPOSITION FOR COMBATTING FUNGUS WITHFUNGICIDALLY-ACTIVE PYRIMIDINE DERIVATIVES This application is acontinuation-in-part of Ser. No. 624,126, filed th March, 1967 nowabandoned.

This invention relates to biologically-active compositions containing asan active ingredient a pyrimidine derivative, to new pyrimidinederivatives, to processes for making new pyrimidine derivatives and tomethods for combating plant and animal pests.

McHattie, in US. Pat. No. 3,287,453, discloses pyrimidine derivatives ofthe formula:

wherein R, R and R, which may be the same or different, stand for alkylor alkenyl radicals of not more than 6 carbon atoms, or wherein R and Rtogether with the adjacent nitrogen atom form a heterocyclic radical,wherein R and R stand for hydrogen or alkyl or alkenyl radicals of notmore than 6 carbon atoms, and wherein X stands for the oxygen or sulphuratom.

Mcl-lattie teaches that some of the compounds possess insecticidalproperties and some of them possess fungicidal properties.

The compounds which possess insecticidal properties are shown to bethose wherein R in the formula above stands for a hydrogen atom, whereasthe only compound shown to possess fungicidal properties ischaracterised by the presence of an n-butyl group at R. Furthermore thefungicidal activity is only demonstrated in the control of one disease,powdery mildew of cucumbers.

We have discovered that if the nature of the substitucnts of thecompounds disclosed by Mcl-lattie in US. Pat. No. 3,287,453 is changed,then the resultant compounds are unexpectedly and remarkably moreeffective as insecticides and fungicides than the Mcl-lattie compounds.

According to the invention we provide a biologicallyactive compositioncomprising as active ingredient a pyrimidine derivative having theformula:

or a salt thereof, wherein either (i) X is an atom of oxygen or sulphur;R is hydrogen; R is hydrogen, alkyl, alkenyl, unsubstituted orsubstituted aryl, cycloalkyl, lower acyl or nitrogencontainingheterocyclic radical; R and R", which may be the same or different, arehy drogen, alkyl, alkenyl or substituted or unsubstituted aryl, and R isalkyl, alkenyl or aryl; or (ii) X is an atom of oxygen or sulphur; R andR which may be the same or different, are alkyl, or alkenyl radicals, ortogether with the adjacent nitrogen atom form a substituted orunsubstituted heterocyclic radical; R is an unsubstituted or substitutedaryl radical; R is hydrogen, or a substituted or unsubstituted alkyl oralkenyl radical; and R is a substituted or unsubstituted alkyl oralkenyl radical; and a carrier for the active ingredient comprising asolid diluent, or a liquid diluent containing a wetting agent.

With reference to (i) above, conveniently, when R R and/or R are alkylor alkenyl, they contain not more than six carbon atoms and when R isalkyl or alkenyl it contains not more than four carbon atoms.Conveniently, when R is an aryl radical it may be a phenyl radical andwhen substituted the substituents may be alkyl or halogen and when R isan aryl radical it may be a phenyl radical.

With reference to (ii) above conveniently, R and R contain not more thansix carbon atoms, R is a phenyl radical, R is a hydrogen or a loweralkyl or alkenyl radical containing not more than six carbon atoms and Ris an alkyl radical which contains not more than four carbon atoms. Thegroup NRR preferably stands for a heterocyclic radical, for example, aheterocyclic radical containing a 5- or 6-membered ring, for example thepiperidino or morpholino radical.

More particularly, therefore, the invention provides a biologicallyactive composition comprising as active ingredient a pyrimidinederivative of the formula:

R5 w l R4 O-P(ORS)2 N N V NR'R or a salt thereof, wherein X is an atomof oxygen or sulphur; R is hydrogen; R is hydrogen, alkyl or alkenylcontaining not more than six carbon atoms; phenyl or halooralkylsubstituted phenyl, cyclohexyl, acetyl, or a nitrogen-containingheterocyclic radical; R is alkyl containing not more than six carbonatoms or a phenyl radical; R is hydrogen, or alkyl or alkenyl containingnot more than six carbon atoms; R is alkyl containing not more than sixcarbon atoms or phenyl; and a carrier for the active ingredientcomprising a solid diluent, or a liquid diluent containing a wettingagent.

Specific pyrimidine derivatives according to the invention are listed inTable I below and all the compounds, except those marked with anasterisk, are new compounds.

It may be noted that the 4- and 6- positions are equivalent.

In this specification the numbering of the pyrimidine 0 ring is asfollows:

As suitable salts of the pyrimidine derivatives of this invention theremay be mentioned, for example, the hy- 65 drochlorides.

NVN

Particularly useful pyrimidine derivatives are those numbered 3, 4, 8,IO, 16, 25, 27, 28, 30, 33 and 34 in Table I above.

The pyrimidine derivatives of the present invention are very toxictowards a variety of invertibrates including molluscs, mosquitoes,mosquito larvae (Aedes aegypti), black aphids (Aphisfabae), green aphids(Mac'- rosiphum pisi), red spider mites (Tetranychus telarius), cottonstainer capsids (Dysdercus fascz'atus), diamond back moth caterpillars(Plutella maculipennis), mustard beetles (Phaea'on cochleariae), commonhouseflies (Musca domestica) and root knot nematodes (Meloidogyneincognim). Furthermore, the pyrimidine derivatives of the invention haveinsecticidal action against insects that prey on animals, for exampleLucilia sericata (sheep blow flies).

The pyrimidine derivatives of the invention also possess activityagainst a wide variety of fungal diseases including, for example, thefollowing specific diseases:

Puccinia recondita (rust) on wheat Pliytuphrlzora infeslans (lateblight) on tomatoes Sp/zaerothecafuliginea (powdery mildew) on cucumberErysiphe graminis (powdery mildew) on wheat and barley Podosphaemleucotricha (powdery mildew) on apple Unc'inula necator (powdery mildew)on vine Plasmopara viticola (downy mildew) on vine Piricularia oryzae(blast) on rice Venturia inaequalis (scab) on apple A particularlyuseful feature of the activity of the pyrimidine derivatives listedabove is their systemic effect, that is to say, their ability to movethroughout a plant to reach any part thereof and to combat any insectinfestation or fungal infection thereon; it is possible with their usetherefore to produce a composition which has valuable systemicinsecticidal and fungicidal activity.

In use, a pyrimidine derivative of the invention or a compositioncontaining the same may be applied in a number of ways. Thus theirapplication can suitably be directed onto the foliage of a plant or toinfected and- /or infested areas thereof; alternatively the soilsurrounding a plant, or soil in which seeds or plants are to be sown orplanted can be treated with a pyrimidine derivative or compositioncontaining the same. If desired,

the seeds themselves can be similarly treated. A pyrimidine derivativeof this invention or a composition containing the same, may also be usedto treat surfaces, for

example in dwellings, to render them toxic towards pests. In veterinaryusage, a pyrimidine derivative or composition containing the same, mayconveniently be administered to any animal for the purpose of combatingan insect infestation.

In a further aspect of the invention we provide a method of combatingundesired insect infestations in animals which comprises administeringto an animal a biologically active composition as hereinbefore definedor a novel pyrimidine derivative as hereinafter defined.

The invention further includes a method of combating plant pests whichcomprises applying to a plant or to seeds thereof a biologically activecomposition as hereinbefore defined or a novel pyrimidine as hereinafterdefined.

In yet a further aspect of the invention, therefore, we provide a methodof treating agricultural soil comprising applying to the soil abiologically active composition as hereinbefore described or a novelpyrimidine derivative as hereinafter defined.

The pyrimidine derivatives and compositions of the invention may be usedfor agricultural, horticultural or veterinary purposes and thederivative or type of composition used in any instance will depend uponthe particular purpose for which it is to be used.

Compositions comprising the invention compounds may be in the form ofdusting powders or granules wherein the active ingredient is mixed witha solid diluent or carrier. Suitable solid diluents or carriers may be,for example, kaolin, pumice, bentonite, kieselguhr, dolomite, calciumcarbonate, talc, powdered magnesia, Fullers earth, gypsum, l-Iewittsearth, diatomaceous earth and China clay. Compositions for dressingseed, for example, may comprise an agent assisting the adhesion of thecomposition to the seed, for example, a mineral oil, or a vegetable oilsuch as castor oil.

The compositions may also be in the form of dispersible powders orgrains comprising, in addition to the active ingredients, a wettingagent to facilitate the disper sion of the powder or grains in liquids.Such powders or grains may include fillers, suspending agents and thelike.

The compositions may also be in the form of liquid preparations to beused as dips or sprays which are generally aqueous dispersions oremulsions containing the active ingredient in the presence of one ormore wetting agents, dispersing agents, emulsifying agents or suspendingagents.

Wetting agents, dispersing agents and emulsifying agents may be of thecationic, anionic or nonionic type. Suitable agents of the cationic typeinclude, for example, quaternary ammonium compounds, for example,cetyltrimethylammonium bromide. Suitable agents of the anionic typeinclude, for example, soaps, salts of aliphatic monoesters of sulphuricacid, for example sodium lauryl sulphate, salts of sulphonated aromaticcompounds, for example sodium dodecylbenzen'esulphonate, sodium, calciumor ammonium lignosulphonate, butyl-naphthalene sulphonate, and a mixtureof the sodium salts of diisopropyland triisopropylnaphthalene sulphonicacids.

Suitable agents of the non-ionic type include, for example, thecondensation products of ethylene oxide with fatty alcohols such asoleyl alcohol or cetyl alcohol, or with alkyl phenols such asoctylphenol, nonylphenol and octylcresol. Other non-ionic agents are thepartial esters derived from long chain fatty acids and hexitolanhydrides, the condensation products of the said partial esters withethylene oxide, and the lecithins.

Suitable suspending agents are, for example, hydrophilic colloids, forexample polyvinylpyrrolidone and sodium carboxymethylcellulose, and thevegetable gums, for example gum acacia and gum tragacanth, andbentonite.

The aqueous dispersions or emulsions may be prepared by dissolving theactive ingredient or ingredients in an organic solvent which may containone or more wetting, dispersing or emulsifying agents and then addingthe mixture so obtained to water which may likewise contain one or morewetting, dispersing or emulsifying agents. Suitable organic solvents areethylene dichloride, isopropyl alcohol, propylene glycol, diacetonealcohol, toluene, kerosene, methylnaphthalene, xylenes,trichloroethylene, methyl chloroform and trimethyl-benzene.

The compositions to be used as sprays may also be in the form ofaerosols wherein the formulation is held in a container under pressurein the presence of a propellant such as fluorotrichloromethane ordic'hlorodifluoromethane.

By the inclusion of suitable additives, for example for improving thedistribution, adhesive power and resistance to rain on treated surfaces,the different compositions can be better adapted for the various usesfor which they are intended.

The pyrimidine derivatives may also be conveniently formulated byadmixing them with fertilizers. A preferred composition of this typecomprises granules of fertilizer material incorporating, for examplecoated with, a pyrimidine derivative. The fertilizer material, may forexample comprise nitrogen or phosphatecontaining substances.

In yet a further aspect of the invention, therefore, we provide afertilizer comprising a pyrimidine derivative as hereinafter defined.

The compositions which are to be used in the form of aqueous dispersionsor emulsions are generally supplied in the form of a concentratecontaining a high proportion of the active ingredient or ingredients,the said concentrate to be diluted with water before use. Theseconcentrates are often required to withstand storage for prolongedperiods and after such storage, to be capable of dilution with water inorder to form aqueous preparations which remain homogeneous for asufficient time to enable them to be applied by conventional sprayequipment. The concentrates may conveniently contain from 10-85% byweight of the active ingredient or ingredients and generally from 25-60%by weight of the active ingredient or ingredients. When diluted to formaqueous preparations, such preparations may contain varying amounts ofthe active ingredient or ingredients depending upon the purpose forwhich they are to be used, but an aqueous preparation containing between0.001% and 1.0% by weight of active ingredient or ingredients may beused.

It is to be understood that the pesticidal compositions of thisinvention may comprise, in addition to a pyrimidine derivative, one ormore other compounds having biological activity.

When used for veterinary purposes, the compositions may be in the formof dips, sprays or dusting powders for external application and thecompositions described above are suitable for this purpose. Theveterinary compositions for external application may also be in the formof a hand dressing prepared from an ointment or cream base, for examplewhite petroleum jelly.

Alternatively, the veterinary compositions of the invention may be in aform suitable for oral administration, for example as tablets, capsules,boluses, suspensions, emulsions or solutions. The compositions for oraladministration may contain conventional excipients, for example inertcarriers, for example calcium phosphate, lubricating agents, for examplemagnesium stearate, and granulating and disintegrating agentsconventionally used in tablet manufacture, for example starch and/orvegetable gums. The suspensions and emulsions may be prepared usingconventional excipients described above.

Alternatively, the veterinary compositions of the invention may be in aform suitable for parenteral administration, for example sterilesolutions, suspensions or emulsions. The compositions for parenteraladministra tion may contain conventional excipients, for examplesolvents, for example water, vegetable oils, or N,N- dimethylacetamide,and excipients described above conventionally used in the preparation ofemulsions and suspensions.

The veterinary compositions of the invention may optionally additionallycontain one or more substances of known veterinary utility, for exampleanthelmintics and/or bactericides. Both the veterinary and agriculturalcompositions of the invention may in addition be stabilised by theincorporation therein of stabilizing agents, for example epoxides, forexample epichlorohydrin.

It is to be understood that the pesticidal compositions of thisinvention may comprise, in addition to a pyrimidine derivative, one ormore other compounds having biological activity.

Compositions according to the invention were made up in the followingmanner and tested against various fungal diseases, and the results ofthese tests are shown in Tables 11 to IV hereinafter. In the tests, botha protectant and an eradicant test were carried out, and in theprotectant test the plants were sprayed so that the leaves were wettedwith a solution or suspension containing 500 parts per million of theactive compound Grading Percentage Amount of Disease 0 61 to l 26 to 602 6 to 25 3 0 to 5 In the tables the first column indicates thepyrimidine derivative used with reference to the numbers in the firstcolumn in Table 1 above. Each of the subsequent columns in the Tableindicates the disease, the host plant, the duration of the test in daysand the protectant (PROT) and eradicant (ERAD) results.

TABLE II Com- Erysiphe Pltyloplzrlzora Puccim'a Plasmupuru UncinulaErysiphe pound No. c'iz'horacearum infesrans recondila Viliculu necalorgranunis Powdery Late Rust Downy Powdery Powdery mildew blight mildewmildew mildew cucumber tomato wheat vine vine wheat l0 days 4 days l0days 7 days 14 days l0 days Prot Erad Prot Prot Eracl Prot Prot Prot l 02 0 3 3 2 O 0 2 O 0 O 3 0 O O O O l O 0 4 l l O l l O 2 3 2 5 2 O O l OO l 3 O 6 O O 2 3 O 0 O 0 7 O 0 0 1 0 O 0 O 3 8 O O O l 2 O O O O 9 O O0 0 0 l 0 2 l0 0 1 O O O l 2 l l l O l l 2 O O O l2 0 0 l O l 0 l 0 3 l30 l O 2 3 0 0 0 l 14 O O 0 l O 0 l5 0 O 2 l O l 1 0 l6 0 O 2 O O 0 TABLEIII Com- Erysiplle* Phyloplxthora Puccinia Plasnwpara Um'inula Erysipllepound No. ciclwraceurum infestans recondim viticula necalor graminisPowdery Late Rust Downy Powdery Powdery mildew blight mildew mildewmildew cucumber tomato wheat vine vine wheat l0 days 4 days 10 days 7days 14 days 10 days Prot Erad Prot Prot Erad Prot Prot Prot l7 0 l O lO O 0 3 l8 3 0 0 O O 0 l9 0 O O l l 0 l 0 3 0 0 l 3 0 0 0 2l 0 l l O 0 l2 O 22 O O l. 3 2 2 l O 23 0 l l 2 l O 2 O O 24 0 0 2 l 0 2 0 O 25 0 l 22 0 O 3 26 O 0 0 0 0 O 0 l 28 0 l l 0 l l 2 29 O O O 0 O 2 O l 30 3 3 OO O 31 l 0 3 0 O 32 1 0 0 33 0 l 0 2 0 O 34 0 l l 0 O O 0 0 35 0 l O O OO O O For compounds 24 to 30 the disease was Sphavmlhewfilligim'a TABLEIV preparations were made by dissolving each of the compounds in amixture of solvents consisting of four parts Coml'Iryvip/u' lmloxphuvraPiriz'uluriu Venluriu by volume of acetone and one part by volume ofdiacepmmd tone alcohol. The solutions were then diluted with N0. gramuusIUUCOHILIHI myzuo umcqualm' powdery powdery Blast scab water containing0.01% by weight of a wetting agent g x i R. A I sold under the tradename of LlSSAPOL NX until ar cy pp c icc pp c 10 days 74 4 days 7 days I4 days the liquid preparations contained the required concen- Prot ProtProt Prot tration of the compound (LISSAPOL is a Trade 1 2 Mark).

2 3 The test procedure adopted with regard to each test 3 3 0 0 0 insectwas basically the same and comprised supporting 32 I U a number ofinsects on some medium which may be a 2x 3 0 3 6O host plant or somefoodstuff on which the insect feeds, 29 3 1 0 and treating either orboth the insect and the medium with the preparations. The mortality ofthe insects was then assessed at periods varying from one to three daysafter the treatment.

The results of the tests are given below in Table V to VII. In theseTables the first column indicates the compound used. Each of thesubsequent columns indicates the name of the test insect, the host plantor medium on which it was supported, and the number of days which wereallowed to elapse after treatment before assessing the percentage ofinsects which had been killed. The assessment is expressed in integerswhich range 3 represents over 90% kill The concentration of theinvention compound in the solutions used was l,OO parts per million forall the pests except in the cases of Aedes aegypla (Tables V to from 0to 3.

0 represents less than km Vll) and Meloidogyne incognita (Table VI) whenthe 1 represents f 30-49% km concentratlon of the invention compound inthe solu- 2 r pr s nts f 5 klll tion used was parts per million.

TABLE V Aedes Ap/n's Macro- Tetranyc/tus Tetranychus Dysdercus PlulellaCalandra Phaedon Musca Comaegypli fabae siphum pisi telarius telariusfasciatus maculipennis granaria coc/rleariae domestica pound Mos- BlackGreen Red spider Red spider Cotton Diamond Grain Mustard House- No.quito aphid aphid mite egg stainer back moth weevil beetle fly capsidcaterpillar Water Broad Broad French French Cotton Cabbage/ WheatMustard] Milk &

bean bean bean bean paper grain paper sugar cotton wool 2 days 2 days 3days 3 days 3 days 2 days 3 days 2 days I day l 3 3 3 3 3 3 0 3 3 3 2 33 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 3 3 3 3 3 3 3 3 3 3 5 3 3 3 3 3 3 3 3 33 6 3 3 3 3 3 3 3 l 3 2 7 3 3 3 3 0 2 3 2 3 3 8 3 3 3 3 3 3 3 3 3 3 9 3l 2 3 3 3 3 3 3 3 l0 3 3 3 3 3 3 3 3 3 3 l l 3 3 3 3 3 3 3 3 3 3 12 3 33 3 0 3 2 0 3 3 l3 3 3 3 3 a 3 3 0 0 0 0 14 3 3 3 3 37.3 3 3 3 l5 3 O l3 0 3 O O 3 3 l6 3 3 3 3 3 3 3 3 3 3 l7 3 3 3 3 0 0 0 0 O 0 l8 3 3 3 3 Ol O O l 0 l9 3 2 3 3 O 0 O 0 0 0 20 O 0 3 0 0 0 0 O 0 0 2| 3 3 3 O 0 0 02 0 22 O l l 3 0 23 3 O 0 0 O 0 0 O l 3 TABLE VI Aedes Aphis Macro-Telranyc/ius Tetranychus Dysdercus Plutella Calandra Phaedon Musz'a Com-Aegypra fabae sip/tum pisi lelurius relarius fasciams maculipenni:granaria cochleariae domestica pound Mos- Black Green Red spider Redspider Cotton Diamond Grain Mustard House- No. quito aphid aphid miteegg stainer back moth weevil beetle fly larva capsid caterpillar WaterBroad Broad French French Cotton Cabbage] Wheat Mustard/ Milk &

bean bean bean bean paper grain paper sugar cotton wool 2 days 2 days 3days 3 days 3 days 2 days 3 days 2 days 1 day 25 3 3 3 3 3 3 3 3 3 3 263 3 3 3 0 O 0 O 0 O 27 3 3 3 3 2 3 3 3 3 3 28 3 3 3 3 3 l 3 O 3 3 29 3 22 3 0 0 0 0 O 0 In addition to the above activity compounds 26 and 27gave a grading of 3 against the pest Meluidogyne incugnim (R00! knolnematode) afier 2 days.

TABLE VII Aedes Aphis Macro- Tetranychus Tetmnyclzus Dysdemus PlutellaCalandra Plzaedon Musca Comaegypti fabae sip/mm pisi lelarius telariusfasciams maculipennis granaria cochleariae domestica pound Mos- BlackGreen Red Spider Red spider Cotton Diamond Grain Mustard House- No.quito aphid aphid mite egg stainer back moth weevil beetle fly larvacapsid caterpillar Water Broad Broad French French Cotton Cabbage/ WheatMustard/ Milk &

bean bean bean bean paper grain paper sugar cotton wool 2 days 2 days 3days 3 days 3 days 2 days 3 days 2 days 1 day 31 3 3 3 3 3 l 0 0 3 3 323 2 2 3 0 2 2 0 O O 33 3 3 3 3 3 3 3 3 3 3 34 3 0 O 3 0 0 0 O 2 2According to a further feature of the invention we provide novelpyrimidine derivatives of the formula:

or a salt thereof, wherein either (i) X is an atom of oxygen or sulphur;R is hydrogen; R is hydrogen, alkyl, alkenyl, unsubstituted orsubstituted aryl, cycloalkyl, lower acyl or nitrogen-containingheterocyclic radical; R and R which may be the same or different, arehydrogen, alkyl, alkenyl or substituted or unsubstituted aryl, and R isalkyl, alkenyl or aryl; provided that R, R and R are not all hydrogen;or (ii) X is an atom of oxygen or sulphur; R and R which may be the sameor different, are alkyl or alkenyl radicals, or together with theadjacent nitrogen atom form a substituted or unsubstituted heterocyclicradical; R is an unsubstituted or substituted aryl radical; R ishydrogen, or a substituted or unsubstituted alkyl or alkenyl radical;and R is a substituted or unsubstituted alkyl or alkenyl radical.

With reference to (i) above preferred and particularly useful pyrimidinederivatives are those wherein R", R and/or R are alkyl or alkenylradicals containing not more than six carbon atoms; R is an alkyl oralkenyl radical containing not more than four carbon atoms.Conveniently, when R is an aryl radical it is a phenyl radical and whensubstituted preferred substituents are alkyl or halogen.

With reference to (ii) above preferred and particularly usefulpyrimidine derivatives are those wherein R and R contain not more thansix carbon atoms, R is a phenyl radical, R is hydrogen or a lower alkylor alkcnyl radical containing not more than six carbon atoms and R is analkyl radical containing not more than four carbon atoms. The group NRRpreferably stands for a heterocyclic radical, for example, aheterocyclic radical containing a 5- or 6- membered ring, for examplethe piperidino or morpholino radical.

More particularly, therefore, ina further aspect the invention providesa pyrimidine derivative of the formula:

or a salt thereof, wherein X is an atom of oxygen or sulphur; R ishydrogen; R is hydrogen, alkyl or alkenyl containing not more than sixcarbon atoms, phenyl or haloor alkylsubstituted phenyl, cyclohexyl,acetyl, or a nitrogencontaining heterocyclic radical; R is alkylcontaining not more than six carbon atoms or a phenyl radical; R ishydrogen, or alkyl or alkenyl containing not more than six carbon atoms;R is alkyl containing not more than six carbon atoms or phenyl.

According to a further feature of the invention, we provide a processfor the manufacture of the said novel pyrimidine derivatives whichcomprises reacting a compound of the formula:

wherein R R R and R have the meanings stated and R is hydrogen or analkali metal atom, with a halogen derivative of the formula:

Y--P (OR wherein R and X have the meanings stated and Y is a halogenatom; if necessary in the presence of a diluent as a reaction medium.

When R stands for an alkali metal atom, it may be, for example, a sodiumor potassium atom. Conveniently Y is, for example, a chlorine or bromineatom.

In the case where R is hydrogen, the starting compound is, conveniently,first converted to the corresponding alkali metal derivative, forexample, by reaction with a solution of sodium in ethanol, or thereaction is carried out in the presence of an acid-binding agent, forexample, an alkali metal salt of a weak acid, for example, an alkalimetal carbonate, for example, potassium carbonate, or a tertiary organicbase, for example, a trialkylamine of not more than 12 carbon atoms, forexample, triethylamine, or an N,N- dialkylarylamine, for example anN,N-dialkylarylamine of not more than 12 carbon atoms, for example N,N-dimethylaniline.

The reaction may conveniently be carried out in an inert diluent orsolvent, for example benzene, ethyl acetate, acetone, methyl ethylketone, methyl butyl ketone, toluene, acetonitrile, or dimethylformamideand it may be accelerated or completed for example by the application ofheat and/or the use of a catalyst.

EXAMPLE 1 The compound 0,0-diethyl-O-(2-amino-5-n-butyl-4-methyl-pyrimid-6-yl) phosphorothionate (Compound no. 18, Table I) havingthe formula:

was prepared as follows:

2-Amino-5-n-butyl-4-hydroxy-6-methy1pyrimidine (7.24 g., 0.04 mole) wasadded to sodium (0.92 g., 0.04 mole) in dry ethanol (40 ml.). Thesolution was kept at 40C for 30 minutes, the solvent removed in vacuo,and the residue dried by azeotropic distillation with benzene.

To the dry residue was added dry benzene l 10 ml. followed bydiethylchlorothiophosphate (0.04 mole), and the mixture stirred andrefluxed overnight. The cooled mixture was shaken with ice-cold aqueoussodium hydroxide solution, washed with water until the washings werealkali-free, dried (Na SO and the benzene removed in vacuo. The residuecrystallised on being allowed to stand, and was recrystallised frompetroleum ether, 4.5 g., m.p. 79-80C.

EXAMPLE 2 The compound 0,0-diethyl-O-(2-n-butylamino-4-methyl-pyrimid-6-y1) phosphorothionate (Compound no. 4, Table 1) havingthe formula:

was prepared as follows:

A mixture of 2-n-butylamino-4-hydroxy-6-methy1- pyrimidine (5g., 0.028mole) and anhydrous potassium carbonate (3.82 g., 0.028 mole) in drybenzene (75 ml.) was stirred and refluxed for 3 hours with azeotropicremoval of water. To the cooled mixture was addeddiethylchlorothiophosphate (0.028 mole), and the reaction mixturestirred and refluxed overnight. The cooled mixture was washed with cold5% aqueous sodium hydroxide solution, and then with water until thewashings were alkali-free. The benzene layer was dried (Na SO and thesolvent removed to leave a viscous oil which was heated at 50C under0.01 mm. for

20 minutes to leave the product as a colourless oil, 4.8 y

EXAMPLE 3 The compound having the formula:

5 1 CH O.P(OCH3).,

(Compound no. 14, Table I) was prepared as follows:

2-Amino-4-hydroxy-6-methylpyrimidine (5 g., 0.04 mole) was suspended indry dimethylformamide, and to the suspension was added, in an atmosphereof nitrogen, sodium hydride (1.92 g., of 50% mineral oil suspension,0.04 mole) a little at a time, allowing the exothermic reaction tosubside before each subsequent addition. Dimethylchlorothiophosphate(0.42 g., 0.04 mole) was then added dropwise with stirring; thetemperature of the reaction mixture rose to 50C during 5 the addition.The mixture was stirred for 1 hour and then poured into water (400 ml.).The product separated as an oil which soon crystallised, and wasfiltered off and dried. Recrystallisation from benzenepetroleum ethergave plates (3 g.) m.p. 106108C. The following compounds of Table Iabove were prepared in a similar manner to Examples 1, 2 or 3.

Com- Prepared by Physical Characteristics of pound No. method ofCompound Example No.

1 1 n 1.5194 2 1 m.p. 103C. Recrystallised from I benzene/petroleumetherv 3 2 n 1.5030 5 2 n 1.5223 6 l m.p. 7678C. Recrystallised frompetroleum ether. 7 1 m.p. 82C. Recrystallised from benzene/petroleumether. 8 1 m.p. 118C. Recrystallised from 25 benzene/petroleum ether.

9 1 n 1.5649 10 2 Red 011. l 1 l m.p. 1 10-1 1 1C. Recrystallised frombenzene/petroleum ether. 12 1 n 1.5757 13 1 m, 1.5631 15 1 m.p. 103C.Recrystallised from benzene/petroleum ether. 16 1 m.p. 96C.Recrystallised from benzene/petroleum ether. 17 1 m.pv 105107C;Recrystallised from 60-80petroleum ether. 19 1 m.p. 76-78C.Recrystallised from petroleum ether.

20 1 m.p. 84C. Recrystallised from petroleum ether. 21 1 m.p. 102C.Recrystallised from benzene/petroleum ether. 22 1 n,, 1.4241 23 1 m.p.102C. Recrystallised from petroleum ether.

24 3 m.p. 92C. Recrystallised from isopropyl alcohol. 25 3 mp. 74C.Recrystallised from isopropyl alcohol. 26 3 m.p. 145-150C.Recrystallised from a mixture of isopropyl alcohol and petroleum ether.

28 3 Viscous liquid (low m.p. solid) 29 3 m.p. 84C. Recrystallised frompetroleum ether. 30 l n 1.5521

EXAMPLE 4 The compound 0,0-diethyl-O-(4-phenyl2- was prepared asfollows: A mixture of 4-hydroxy-6- phenyl-2-piperidinopyrimidine (2.55g., 0.01 mole), triethylamine (1.01 g., 0.01 mole) anddiethylchlorothiophosphate (1.89 g., 0.01 mole) in dry benzene (50 ml.)was refluxed overnight. The mixture was allowed to cool, filtered, andthe filtrate washed with ice-cold 5% sodium hydroxide solution, and thenwith water until the washings were alkali-free, and the benzene layerdried (Na- SO Removal of the solvent gave a viscous oil whichcrystallised on being allowed to stand. Recrystallisation from petroleumether (60-80) gave the product, m.p. 55C. (3.2 g., 78%).

EXAMPLE 5 The compound (Compound no. 31 of Table I) having the formula:

n/ (cc n was prepared as follows:

A mixture of 4-hydroxy-2-morpholinophenylpyrimidine (5 g., 0.019 mole)and anhydrous potassium carbonate (2.69 g., 0.019 mole) in dry benzene(60 ml.) was stirred and refluxed with azeotropic removal of water for 2hours. To the cooled mixture was added diethylchlorothiophosphate (3.68g., 0.019 mole) and the reaction mixture stirred and refluxed for 16hours. The cooled mixture was washed with cold 5% aqueous sodiumhydroxide solution, washed with water until the washings werealkali-free and the benzene layer dried (MgSO Removal of the solventgave the product, recrystallised from petroleum ether, 2 g., m.p.64-66C.

The following compounds of Table l above were prepared in a similarmanner to the method used in Example 2.

Compound Nu. Refractive Index The compound0,0-diethyl-O-(Z-dimethylamino-S- ethyl-4-phenylpyrimid-6-yl)phosphorothionate (Compound no. 36, Table I) having the formula:

was prepared as follows: v 2-Dimethylamino-5-ethyl-4-hydroxy-6-phenylpyrimidine (4.87 g., 0.02 mole) was added to a solution of sodium(0.46 g., 0.02 mole) in dry ethanol (50 ml.). The solution was kept at40C for 20 minutes, the solvent removed in vacuo, and the residue driedby azeotropic distillation with benzene. To the dry residue was addeddry benzene (50 ml.) followed by diethylchlorothiophosphate (3.3 ml.,0.02 'mole) and the mixture was stirred and refluxed overnight. Thecooled mixture was shaken with ice-cold 5% aqueous sodium hydroxidesolution, washed with water until the washing were alkali-free, dried(Na SO and the benzene removed in vacuo. The residue was heated at 40Cand under 0.01 mm. for 20 minutes to remove volatile materials leavingthe product as a pale yellow oil, n 1.5727, 4.3 g..

EXAMPLE 7 Compound No. 6 (Table 1) 25.0 LUBROL" L (alkylphenol/ethyleneoxide condensate; LUBROU is a Trade Mark) 2.5 Calciumdodecylbenzenesulphonate 2.5 AROMASOL" H (alkylbenzene solvent;AROMASOL" is a Trade Mark) 70.0

EXAMPLE 8 This example also illustrates a concentrate which is in theform of a miscible oil. The composition of this concentrate is asfollows:

Compound No. 6 (Table I) 25.0 LUBROL" L (LUBROL is a Trade Mark) 4.0Calcium dodecylbenzenesulphonate 6.0 AROMASOL" H(AROMASOL" is a Trade65.0 Mark) EXAMPLE 9 This example illustrates a wettable powder havingthe following composition:

Compound No. 6 (Table l) 25.0 Sodium silicate 5.0 Calciumlignosulphonate 5.0 China clay 65.0 100.0

EXAMPLE This example illustrates an atomisable fluid comprising amixture consisting of 25% by weight of the Compound no. 6 (Table l) and75% by weight of xylene.

EXAMPLE 1 1 This example illustrates a dusting powder which may beapplied directly to plants or other surfaces and comprises 1% by weightof the Compound No. 6 (Table l) and 99% by weight of talc.

EXAMPLE l2 EXAMPLE 13 The ingredients listed below were ground togetherin the proportions stated to produce a powdered mixture readilydispersible in liquids.

Compound No. 6 (Table l) 50% DlSPERSOL" T (DlSPERSOL" is a Trade Mark)5% China clay 45% 100% EXAMPLE 14 A composition suitable for use as aseed dressing was prepared by mixing all three of the ingredients setout below in the proportions stated Compound No. 6 (Table I) 80 Mineraloil 2 China clay l8 100% EXAMPLE A granular composition was prepared bydissolving the active ingredient in a solvent, spraying the solutionobtained onto the granules of pumice and allowing the solvent toevaporate.

Compound No. 6 (Table l) 5 Pumice granules 95 100% EXAMPLE 16 Thecompounds numbered 3,4,8,10,16,25,27,28,30,33 and 34 in Table 1heretofore were formulated in the same manner as set out in Examplenumbers 7 to 15 above.

EXAMPLE 1 7 The following test was used to evaluate the fungicidalactivity of compounds disclosed by McHattie in U.S. Pat. No. 3,287,453,in comparison with the invention compounds against four fungal diseaseof plants.

The McHattie compounds are hereinafter designated as compounds A, B, C,D and E, and have the following formulae:

COMPOUND A COMPOUND B COMPOUND C COMPOUND D N N V COMPOUND E Theprocedure used was identical to that detailed hereinabove in respect ofthe invention compounds, except that only the protectant tests werecarried out.

The results, graded as hereinabove, are given in the following Tables,one for each disease.

Protectant test against the disease brown rust of wheat lucc'iniurez'mrdilu) McHattie Grading Invention Grading Compound Compound A 6 3 B0 8 2 C 0 l3 3 D 25 2 E l Protectant test against the disease powderymildew of cucumbers lfrysiplre c'it'lwruccarum Mcl-lattie GradingInvention Grading Compound Compound A 0 5 2 B 0 l8 3 C 0 D 0 E 3Protectant test against the disease late blight of tomatoes P11\-/0ph!/mra iufesluns) The above results clearly demonstrate that a highlevel of fungicidal activity is shown by the invention com pounds, andthat the McI-Iattie compounds (except compound E) are devoid of any suchactivity.

EXAMPLE I 8 The following procedure was used to evaluate the fungicidalactivity of the McI-lattie compound E and the compound No. 5 against thefungal disease Venturia inaequalis (apple scab).

An aqueous preparation containing the chemical to be evaluated wasprepared by dissolving the chemical in a little diacetone alcohol anddiluting the solution thus obtained with water containing 0.1% of awetting agent until the preparation contained 1000 ppm. (parts permillion) of the chemical. Aliquots of this preparation were then furtherdiluted with water to obtain preparations containing 500,125, 25 and I0ppm. of the chemical.

The preparations were then sprayed onto the foliage of young appleplants to wet the foliage, care being taken to prevent any of thepreparation entering the soil in which the apple plants were growing.Two replicates were used for each chemical and for each rate ofapplication.

24 hours later the plants were infected with the disease Venturiainaequalis, and after a further period of 21 days, the extent of diseasewas visually assessed by comparison with untreated plants which had beeninfected at the same time as the treated plants.

The results of the above evaluation are given in Table A below, whereinthe extent of disease is given as a grading from 0 to 3 wherein thegradingrepresents amount of disease expressed as a percentage of theamount of disease in the untreated plants.

(ppm) Compound N0. 5 McHattie Compound E These results demonstrate thesuperior performance of an invention compound of the present applicationover the McHattie compound E. This is surprising finding in particularbecause all the work in this field so far has indicated that chemicalsof this type are active only against the powdery mildew disease of appletrees at commercially usable rates of application. Since Venturiizinaequalis is not a powdery mildew, the unexpected activity of theinvention compound against this disease at commercially usable rates ofapplication now renders it feasible to protect apple trees againstattacks of both powdery mildew (Podosphaera leucotric/za) and apple scab(Venturia inaequalis) by the application of a single chemical.

EXAMPLE 19 The following procedure was used to evaluate the systemicfungicidal activity of the McHattie compound E and the compound no 30against the disease Erysiphe graminis (powdery mildew of wheat).

Preparations containing 1000, 500, 125, and 25 ppm of the chemical to beevaluated were prepared in the manner described in the previous example.

Wheat seedlings, free from disease, were grown in small pots, therebeing from to 8 seedlings in each pot. The preparation (10 cc.) wasabsorbed into the soil in which the seedlings were growing, care beingprevious example and are given in Table B below.

TABLE B Rate of application of chemical Grading (ppm.) Compound No.McHattie Compound E The results indicate that a surprising andremarkable degree of control of the disease has been achieved byapplication to the soil of an invention compound whereas the McHattiecompound E has completely failed to control the disease when applied ina similar manner, even at rates considerably in excess of those whichwould be commercially useful. The control shown by the inventioncompound is of a systemic nature, an activity not predicted in any wayby the Mcl-lattie reference, U.S. Pat. No. 3,287,453.

Where in the foregoing specification a chemical structure has been givenshowing an unsubstituted or monosubstituted amino-pyrimidine atautomeric structure of an imino pyrimidine is to be included within thescope of the invention in any case where such tautomerism takes place. I

What I claim is:

1. A method of combating fungus of plants and animals which comprisesapplying to the fungus a pyrimidine derivative of the formula:

W9 0 CH 0 i 2. A fungicidally active composition comprising as activeingredient afungicidally effective amount of a pyrimidine derivative ofthe formula:

nC H

ll 0 O 1? 3 NHC H

1. A METHOD OF COMBINATING FUNGUS OF PLANTS AND ANIMALS WHICH COMPRISESAPPLYING TO THE FUNGUS A PYRIMIDINE DERIVATIVE OF THE FORMULA:
 2. Afungicidally active composition comprising as active ingredient afungicidally effective amount of a pyrimidine derivative of the formula: